In contrast to the many viruses that block antigen presentation by MHC class I, only a handful appear to block presentation by MHC class II. I don’t understand why any would try to block MHC class II in the first place, but another example of it has just been published.

A little background: Major histocompatibility complexes (MHC) are recognized by T cells. T cells come in several flavors, the best-understood of which are CD4 (T Helper) and CD8 (cytotoxic T lymphocyte; CTL) lymphocytes. CD8 T cells are fairly specialized to deal with cells infected with viruses;1 they recognize MHC class I. CD4 T cells are at the top of the adaptive immune response; they coordinate subsequent responses, by calling in other cell types, driving antibody or CTL responses, and so on.

MHC class I is on the surface of most cells, as you’d expect, because most cells can be infected with viruses. MHC class I is, among other things, a way of directing the CTL attack to the appropriate, virus-infected, cell, and so they deal, fairly strictly, with what’s going on inside their own particular cell. They don’t take up proteins from outside the cell, because then the cell might get killed when it’s actually a neighbor that’s infected. 2

MHC class II, on the other hand, is a general alarm call that signals “Something’s invading the body, somewhere”. MHC class II is only on a limited number of cells, but those cells do take up protein from outside themselves and show it to CD4 T cells. Presentation on MHC class II does not mean that the particular cell is infected.

So it’s quite logical that viruses would be interested in blocking MHC class I, and as I say there are now many examples of viruses that do so. It’s also logical for viruses to want to block MHC class II, since doing so would reduce all the immune responses against them — antibodies, T cells, whatever.

But how would that work? Again: The cells that do MHC class II antigen presentation are not necessarily infected cells. If a virus is going to block MHC class II, it would have to go out of its way infect the MHC class II-presenting cells (known as professional antigen-presenting cells; APC). Not only that, it would probably have to infect a lot of them, to make a real impact on the overall CD4 T cell response, because even a few unaffected APC will drive a fairly significant immune response, making the suppressed ones irrelevant.

So even though viruses might “want” to block MHC class II, there are practical problems that make it hard to do. Nevertheless, there are a couple of viruses who have genes that can block MHC class II. Human cytomegalovirus is the clearest example, I think,3 and several groups have shown that vaccinia virus blocks MHC class II presentation in infected cells.4 Now a paper in Virology5 argues that the vaccinia gene catchily called “A35” is responsible for this block. Since close relatives of A35 are present in many other poxviruses, MHC class II blockade may be widespread in this family.

The data are reasonably convincing, though there are some complications. 6 But I’m still puzzled by how this is supposed to work. Vaccinia virus, and poxviruses in general, aren’t renowned for infecting dendritic cells and macrophages, which are the cell types they’d have to efficiently target if MHC class II blockade was to help them.

Which is consistent with a blockade of MHC class II, true, but if you have reduced viral replication for any reason you’d also expect reduced immune responses, because there would be less viral antigen to drive the response. That is, even though A35 blocks MHC class II, and A35 increases virulence, I’m not convinced that A35 increases virulence because it blocks MHC class II. Viral proteins are notoriously multifunctional, and I wonder if the MHC class II blockade is just one function of A35; or perhaps even if it’s just a side-effect of the “real” virulence function.

I’m open to the notion that A35 (and other viral proteins) are true MHC class II blockers, and that this is functionally important, but I’d like to see more data before I put it in the bank.

The role of phospholipids in vaccinia entry published in Science was recently confirmed and expanded upon by none other than Bernard Moss, head of the lab of viral diseases at NIAID, in a paper titled, Appraising the apoptotic mimicry model and the role of phospholipids for poxvirus entry, (PNAS, Sept 2009).

These observations should be considered with what is now a large body of evidence demonstrating that exposed PS, an early hallmark of apoptosis, is now understood to be a fundamental inhibitor of an inflammatory response, and an inducer of anti-inflammatory cytokines.

As the apoptotic process was likely necessary to evolve to allow for the possibility of metazoans, could viruses be exploiting what may be our most ancient and basic sign of “self”?

A thorough and open access review on the topic oof PS being immunosuppressive, exploited by many pathogens, and is a promising therapeutic target, was just published last month by a group in Germany who have been targeting PS as potential therapy against enveloped viruses, titled: Phospholipids: Key Players in Apoptosis and Immune Regulation, (Gaipl et al, Molecules).

Meanwhile, other scientists are finding that targeting PS with monoclonal antibodies has broad therapeutic potential against vaccinia and other enveloped viruses, and infected cells (which also expose PS), (Soares et al, Nature Medicine, December 2008), titled: Targeting Inside-Out Phosphatidylserine as a Therapeutic Strategy For Viral Diseases.

The Nature Medicine paper concludes:

“Phosphatidylserine on virions and virally infected cells may enable viruses to evade immune recognition and dampen inflammatory responses to infection.”

“In conclusion, targeting PS on cells infected with multiple different viruses and on virions themselves shows promise as an anti-viral strategy. Because anionic phospholipids on virus-infected cells are host-derived and independent of the viral genome, the acquisition of drug resistance should be less problematic than with agents that target virus-encoded components.”

– now wouldn’t that be nice…

MT

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